Hirschsprung Disease Genetic Study

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government.
Know the risks and potential benefits of clinical studies and talk to your health care provider before participating.
Read our disclaimer for details.

Hirschsprung disease is a genetic condition caused by lack of nerve cells in varying lengths of the intestines. This study will investigate the complex genetic basis of the disease, which involves multiple interacting genetic factors.

Condition or disease

Intervention/treatment

Hirschsprung Disease

Other: Identification of genetic causes of Hirschsprung Disease

Detailed Description:

Hirschsprung disease (HSCR) is a birth defect resulting from the absence of nerve (ganglion) cells in the gastrointestinal tract. Hirschsprung disease has a population incidence of 1/5000 live births and most often occurs as an isolated condition. However, approximately 30% of HSCR cases are associated with other birth defects such as Down syndrome, deafness, hypopigmentation, and congenital central hypoventilation syndrome. Hirschsprung disease is a genetic condition with autosomal dominant, autosomal recessive, and multigenic patterns of inheritance described.

Dr. Aravinda Chakravarti's laboratory at Johns Hopkins University has been investigating the genetics of Hirschsprung disease (HSCR) for more than twenty five years. The goal of this research study is to identify genes harboring causative HSCR mutations and to better understand the complex inheritance of HSCR in families by whole genome mapping and sequencing studies. Specifically, the study aims to determine the frequency with which mutations in any human gene lead to familial and isolated forms of HSCR. Further, the study will collect clinical information and investigate possible genotype - phenotype correlations.

Molecular analysis using markers and sequencing, and statistical analysis of these data will be used to identify regions of human chromosomes where putative HSCR disease genes may be located. In addition, the DNA sequence of known and/or suspected HSCR genes will be assessed in individual patients and their family members, in search of causative HSCR susceptibility variants and variants that may affect presentation of the disease and treatment outcomes. Phenotypic information will include pathology, surgical, and other clinical outcomes related to Hirschsprung disease. This study will hopefully lead to a better understanding of the genetics of HSCR and, further down the road, improved diagnosis, treatment, and genetic counseling.

Individuals with Hirschsprung disease and their affected and unaffected relatives.

Other: Identification of genetic causes of Hirschsprung Disease

Blood, saliva, or DNA samples are requested from all study participants. The blood or saliva samples are used to isolate DNA in all participants. Blood samples are also used to establish cell lines in some participants.

Discovery and characterization of common genetic variation associated with Hirschsprung disease [ Time Frame: DNA is isolated up to 1 year after enrollment ]

Genome-wide assays of common genetic variation will be assessed using single nucleotide polymorphism (SNP) arrays

Discovery and characterization of copy number variants associated with Hirschsprung disease [ Time Frame: DNA is isolated up to 1 year after enrollment ]

Copy number variation will be detected using next generation sequencing data and high resolution microarrays that allow for detection of copy number variants across the genome

Discovery and characterization of rare genetic variation associated with Hirschsprung disease [ Time Frame: DNA is isolated up to 1 year after enrollment ]

Exome sequencing will be used to detect rare variation across all genes in the genome

Secondary Outcome Measures
:

Correlation of genetic variants with location of transition zone in Hirschsprung disease [ Time Frame: Baseline pathology data is obtained up to 1 year after enrollment ]

Pathology records and surgical records will be used to determine transition zone

Correlation of genetic variants with risk for enterocolitis in Hirschsprung disease [ Time Frame: Baseline clinical data is obtained up to 1 year after enrollment ]

Characterization of Hirschsprung disease that co-occurs with a known chromosomal disorder [ Time Frame: Baseline clinical data is obtained up to 1 year after enrollment ]

Characterization of Hirschsprung disease that co-occurs with a known single gene syndrome [ Time Frame: Baseline clinical data is obtained up to 1 year after enrollment ]

Characterization of Hirschsprung disease that co-occurs with other congenital anomalies without a known diagnosis [ Time Frame: Baseline clinical data is obtained up to 1 year after enrollment ]

Correlation of genetic variants with need for repeat pull-through surgery in Hirschsprung disease [ Time Frame: Baseline clinical data is obtained up to 1 year after enrollment and follow up data is obtained up to 100 years after enrollment ]

Assessment of complications that lead to eventual repeat pull-through surgery

Correlation of genetic variants with difficulty controlling stools after pull-through surgery [ Time Frame: Baseline clinical data is obtained up to 1 year after enrollment and follow up data is obtained up to 100 years after enrollment ]

Correlation of genetic variants with chronic constipation after pull-through surgery [ Time Frame: Baseline clinical data is obtained up to 1 year after enrollment and follow up data is obtained up to 100 years after enrollment ]

Biospecimen Retention: Samples With DNA

Study volunteers are asked to provide blood or cheek swab/saliva samples. DNA is extracted from the samples for use in the study.

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

Ages Eligible for Study:

up to 100 Years (Child, Adult, Senior)

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Sampling Method:

Non-Probability Sample

Study Population

The study population includes individuals with Hirschsprung disease and their family members.

Criteria

Inclusion Criteria:

- Individuals with Hirschsprung disease and their first degree relatives (any segment length of disease, with or without other congenital anomalies or health problems, single or multiple affected individuals in family)